CN1798750A - Thiadiazine derivatives and use thereof as positive ampa receptor modulators - Google Patents
Thiadiazine derivatives and use thereof as positive ampa receptor modulators Download PDFInfo
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- CN1798750A CN1798750A CNA200480014886XA CN200480014886A CN1798750A CN 1798750 A CN1798750 A CN 1798750A CN A200480014886X A CNA200480014886X A CN A200480014886XA CN 200480014886 A CN200480014886 A CN 200480014886A CN 1798750 A CN1798750 A CN 1798750A
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- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000007334 memory performance Effects 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000001871 perforant pathway Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- FWQHRZXEQNUCSY-UHFFFAOYSA-N tert-butyl N-[2-(ethoxycarbonylamino)-5-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate Chemical compound CCOC(=O)NC1=C(C=C(C=C1)N(CC#C)CC2=CC=C(C=C2)F)NC(=O)OC(C)(C)C FWQHRZXEQNUCSY-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to thiadiazine derivatives and to the use thereof as positive AMPA receptor modulators. More specifically, the invention relates to compounds having formula (I), wherein: A represents a thienyl, furyl, pyrrolyl, oxathiole, thiazole, isothiazole, oxazole or imidazole group; -. represents a single bond or a double bond; R1 represents a hydrogen atom, a linear or branched (C1-C6) alkyl group which is optionally substituted by one or more halogen atoms, or a (C1-C6) alkoxy (C1-C6) alkyl group; R2 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group which is optionally substituted by one or more halogen atoms; and R3 represents a hydrogen atom or a group which is selected from linear or branched (C1-C6) alkyl, CONHR' or SO2NHR', in which R' represents a linear or branched (C1-C6) alkyl group. The invention also relates to the enantiomers and diastereoisomers of the above-mentioned compounds as well as to the pharmaceutically-acceptable base or acid addition salts thereof. The invention further relates to the use of same as medicaments.
Description
The present invention relates to new thiadiazine compound, their preparation method and the pharmaceutical composition that contains them.
People recognize have excitatory amino acid, particularly L-glutamic acid all to play crucial effects in the physiological process of neuron plasticity and in the learning and memory mechanism.Pathologic, physiologic research has clearly shown the defective of L-glutamic acid energy neurotransmission and development closely related (Neuroscience and Biobehavioral Reviews, 1992,16, the 13-24 of Alzheimer; Progress inNeurobiology, 1992,39,517-545).
In addition, in recent years part Study proved the existence of excitatory amino acid receptor hypotype and the interaction of their functions (Molecular Neuropharmacology, 1992,2,15-31).
In these acceptors, the degree that AMPA (alpha-amino group-3-hydroxy-5-methyl base-4-isoxazole-propionic acid) acceptor can participate in physiology neuronal excitation phenomenon is the highest, particularly those and memory process related phenomena.For example, confirmed to learn relevant with the increase of the receptors bind of AMPA and their hippocampus (be used in the brain remembering with means of identification one of must the zone).Equally, recently nootropics (nootropicagent) as aniracetam be considered to be used for forward regulate the neuronal cell ampa receptor (Journal of Neurochemistry, 1992,58,1199-1204).
In the literature, the compound with benzamide structure be described to have this same mechanism of action and can improve the compound of memory performance (Synapse, 1993,15,326-329).Particularly BA 74 is active one of tools in these new pharmacology medicines.
At last, patent specification EP 692 484 has described a benzothiadiazine compounds that AMPA electric current (current) is had promoter action, has then described the concrete benzothiadiazine compounds as the ampa receptor conditioning agent among the patent application WO 99/42456 especially.
Thiadiazine compound involved in the present invention, except being that they also all have surprising pharmacological activity to AMPA stream new this feature, and its activity significantly be better than before the described compound in this area with similar structures.They can be used as the AMPA conditioning agent, are used for the treatment of or prevention and age, anxiety or depressibility syndrome, carrying out property neurodegenerative disease, Alzheimer, pik disease, Huntington Chorea, schizophrenia, the sequela of acute neurodegenerative disease, memory and cognitive disorders that the local asphyxia sequela is relevant with the epilepsy sequela.
More particularly, the present invention relates to the additive salt of formula (I) compound, their enantiomer and diastereomer and they and pharmaceutically acceptable acid or alkali,
Wherein:
◆ A forms with two carbon atoms that carry it:
Be selected from group A
1, A
2And A
3Thienyl, furyl or pyrryl group:
Wherein X represents sulphur, oxygen or nitrogen-atoms and R in each case
aAnd R
bCan be identical or different, represent hydrogen atom, straight or branched (C respectively independently of one another
1-C
6) alkyl group (optional replaced by one or more fluorine atoms), straight or branched (C
1-C
6) alkoxy base, halogen atom, oh group, amino group be (optional by straight or branched (C
1-C
6)-alkyl-carbonyl group, one or two straight or branched (C
1-C
6) alkyl group replaces), carboxylic group or straight or branched (C
1-C
6) alkoxycarbonyl groups,
Be selected from group A
4, A
5, A
6And A
7Oxygen thia cyclopentenes group:
R wherein
aDefinition as mentioned,
Be selected from group A
8And A
9Thiazolyl group:
R wherein
aDefinition as mentioned,
Be selected from group A
10And A
11The isothiazole group:
R wherein
aDefinition as mentioned,
Be selected from group A
12, A
13, A
14And A
15The oxazole group:
R wherein
aDefinition as mentioned,
Perhaps formula A
16Imidazole group:
R wherein
aDefinition as mentioned,
◆
Represent singly-bound or two key,
◆ R
1Represent hydrogen atom, optional by the straight or branched (C of one or more fluorine atoms or one or more halogen atom replacements except fluorine
1-C
6) alkyl group, perhaps (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl group, wherein each moieties can be straight or branched,
◆ R
2Represent hydrogen atom or optional by the straight or branched (C of one or more fluorine atoms or a plurality of halogen atoms replacements except fluorine
1-C
6) alkyl group,
◆ R
3Represent hydrogen atom or be selected from following group: straight or branched (C
1-C
6) alkyl, CONHR ' and SO
2NHR ', wherein R ' represents straight or branched (C
1-C
6) alkyl group.
In mentioned pharmaceutically acceptable acid, including, but not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, dextrocamphoric acid or the like.
In mentioned pharmaceutically acceptable alkali, including, but not limited to sodium hydroxide, potassium hydroxide, triethylamine, uncle-butylamine or the like.
Group A is preferably and is selected from group A
1, A
2And A
3Thienyl group, wherein X represents sulphur atom.
Even more preferably, group A is preferably and is selected from group A
1And A
2Thienyl group, wherein X represents sulphur atom.
Radicals R
aAnd R
bPreferably, independently of one another, be hydrogen atom or chlorine atom.
Radicals R
1Be preferably hydrogen atom or straight or branched (C
1-C
6) alkyl group, be preferably methyl, ethyl or isopropyl group.
Radicals R
2Be preferably hydrogen atom.
Radicals R
3Be preferably hydrogen atom or CONHR ' group, wherein R ' defines suc as formula (I).
Preferred compound of the present invention is:
6-chloro-4-ethyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1, the 1-dioxide,
6-chloro-4-sec.-propyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1, the 1-dioxide,
5,7-two chloro-4-methyl-3,4-dihydro-2H-thieno-[3,4-e] [1,2,4] thiadiazine 1,1-dioxide.
The present invention also relates to be used for the method for preparation formula (I) compound, it is characterized in that with formula (II) compound be raw material:
Wherein A and
Suc as formula (I) definition,
In the presence of formula (III) compound, with the cyclisation of described formula (II) compound:
R
2-C(OMe)
3 (III)
R wherein
2Suc as formula (I) definition, obtain formula (IV) compound:
Wherein A, R
2With
As hereinbefore defined,
Make formula (IV) compound then:
● with the reductive agent reaction, obtain formula (I/a) compound, the object lesson of a formula (I) compound:
Wherein A, R
2With
As hereinbefore defined,
Described formula (I/a) compound is optional to obtain the formula V compound with the reaction of two carbonic acid two (tert-butyl) esters:
Wherein Boc represents group uncle-butoxy carbonyl and A, R
2With
As hereinbefore defined,
Described formula V compound and the reaction of formula (VI) compound:
R’
3-Y
3 (VI)
R ' wherein
3Represent straight or branched (C
1-C
6) alkyl group or CONHR ' or SO
2NHR ' group, wherein R ' defines suc as formula (I), and Y
3Represent leavings group ' obtain formula (I/b) compound behind the deprotection, be an object lesson of formula (I) compound:
Wherein A, R
2, R '
3With
● perhaps in alkaline medium, react with formula (VII) compound:
R’
1-Y
1 (VII)
R ' wherein
1Representative is optional by the straight or branched (C of one or more fluorine atoms or the replacement of a plurality of halogen atom
1-C
6) alkyl group, and Y
1Represent leavings group, obtain formula (VIII) compound:
Wherein A, R '
1, R
2With
As hereinbefore defined,
Described formula (VIII) compound and reductive agent reaction obtain formula (I/c) compound, are an object lesson of formula (I) compound:
Wherein A, R '
1, R
2With
As hereinbefore defined,
Described formula (I/c) compound is optional to react with formula mentioned above (VI) compound, obtains formula (I/d) compound, is an object lesson of formula (I) compound:
Wherein A, R '
1, R
2, R '
3With
As hereinbefore defined,
Described formula (I/a)-(I/d) compound has been formed the whole of formula (I) compound, if desired, can be according to the purification technique of routine, with these compound purifying, if desired, can they be separated into their enantiomer or diastereomer according to the isolation technique of routine, and they can be converted into if desired, the additive salt of they and pharmaceutically acceptable acid or alkali.
The compounds of this invention, except being new this feature, also has ampa receptor activation character, this make they on treatment cognitive defect relevant and schizophrenia with brain aging and nerve degeneration effectively, dull-witted under described cognitive defect such as Alzheimer, Parkinson's disease, pik disease, cobb's disease, volume and the cortex.
The present invention also relates to comprise the pharmaceutical composition of at least a formula (I) compound as activeconstituents and one or more suitable inert non-toxic excipients.In pharmaceutical composition of the present invention, more preferably those are suitable for the composition of oral, parenteral (intravenously or subcutaneous) or nasal administration, comprise tablet, sugar-coat agent, sublingual tablet, gelatine capsule, lozenge, suppository, creme, paste, skin gel agent, injection formulations, drinkable suspensoid etc.
The dosage that uses can be different according to character, severity, route of administration and patient's age and the body weight of disorder.Dosage does not wait from 0.01 to 500mg every day usually, can be in single or divided doses.
The following example is used to illustrate the present invention, but is not used in restriction the present invention.
Starting raw material is known or can prepares according to currently known methods.
The structure of the compound described in the embodiment is (infrared rays, NMR, the mass spectrum) measured according to the spectrophotometry of routine.
Preparation 1:6-chloro-4H-thieno-[3,2-e] [1,2,4] thiadiazine 1, the 1-dioxide with 250mg 3-amino-5-chloro-2-thiophenesulfonamide hydrochloride (J.Med.Chem., 2002,4171-4187) place the triethyl orthoformate of 2.5ml.In about 60 ℃, heated solution 30 minutes.Form the particulate state yellow mercury oxide, collect after filtration, with ether washing and dry.
Fusing point: 260-262 ℃
IR(KBr)：3214，3103，3061，2926，1602，1569，1515，1446，1378，1366，1287，1220，1177，1147，978，840，824，750，628，543cm
-1
Preparation 2:5,7-two chloro-4H-thieno-[3,4-e] [1,2,4] thiadiazines 1,1-dioxide
Steps A: 2,5-two chloro-4-nitros-3-thiophene SULPHURYL CHLORIDE
The mixture of 30ml sulfuric acid and 30ml nitrosonitric acid is cooled off with the salt ice bath.With 10g 2,5-two chloro-3-thiophene SULPHURYL CHLORIDE slowly add in the mixture.In stirring at room solution 3 hours.Then solution is inclined to ice.Collect the little yellow mercury oxide that forms after filtration, wash with water and drying.
IR(KBr)：3525，3410，2917，1673，1552，1442，1388，1176，1085cm
-1
Step B:2,5-two chloro-4-nitro-3-thiophenesulfonamides
The compound of 11g steps A mentioned above is dissolved in the 150ml diox.This drips of solution is added in 300ml 10% solution of ammonium hydroxide.After one hour, reduction vaporization ammonia is with diox.Filter and collect the white precipitate that forms, wash with water and drying.
Fusing point: 125-126 ℃
IR(KBr)：3390，3291，1541，1505，1440，1369，1170，1090cm
-1
Step C:4-amino-2,5-two chloro-3-thiophenesulfonamides
The compound of 7.25g step B mentioned above is placed the mixture of 1: 1 the ethanol/water of 375ml.Heated solution to product dissolves.Add 4.5g ammonium chloride and 15g iron powder then in turn.Reflux after 10 minutes termination reaction.Remove by filter insolubles also with a spot of hot ethanol washing.Reduction vaporization filtrate.Filter and collect the cream-coloured precipitation that forms, wash with water dry then.
Fusing point: in about 120 ℃ of decomposition
IR(KBr)：3440，3412，3354，3290，1600，1557，1336，1318，1166，1125cm
-1
Step D:5,7-two chloro-4H-thieno-[3,4-e] [1,2,4] thiadiazines 1,1-dioxide
The compound of 250mg step C mentioned above is dissolved in the 2.5ml trimethyl orthoformate.In the container that opens wide, solution is heated to boiling.1.5 after hour, reaction is finished.Cooling solution obtains cream-coloured precipitation, collects after filtration, with ether washing and dry.
Fusing point: 200-203 ℃.
Embodiment 1:6-chloro-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
The compound of 196mg preparation 1 is placed 4ml water.The NaBH that slowly adds 500mg
4After 15 minutes, reaction is finished.PH with solution transfers to 5-6 then, and uses the dichloromethane extraction product.Organic phase is through dried over mgso, then reduction vaporization.Residue is dissolved in small amount of methanol, adds entry then and makes the product precipitation.Filter and collect product, wash with water dry then.
Fusing point: 154-156 ℃.
Embodiment 2:6-chloro-4-methyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
Steps A: 6-chloro-4-methyl-4H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
The compound of 250mg preparation 1 is placed 5ml acetonitrile and 0.5ml dimethyl formamide.Add 500mg salt of wormwood, add the 0.3ml methyl-iodide then.In about 7 hours of about 55 ℃ of heated solutions.After reaction finished, removal of solvent under reduced pressure was also water-soluble with residue.Insolubles is collected after filtration fast, washes with water and drying.
Fusing point: 252-254 ℃.
IR(KBr)：3091，2943，1607，1519，1485，1434，1390，1297，1150，1107，1059，1015，835，778，754，570，541cm
-1
Step B:6-chloro-4-methyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
The compound of 200mg steps A mentioned above is dissolved in the 5ml Virahol.Then in about 60 ℃ of heated solutions, and then add the NaBH of 400mg
4After 20 minutes, removal of solvent under reduced pressure, residue is water-soluble.To about 5-6, product is with 3 * 10ml chloroform extraction with pH regulator.Organic phase is through dried over mgso, filtration, concentrating under reduced pressure then.Residue is dissolved in minimum of chloroform, adds the hexane precipitated product.Filter and collect product, with hexane wash and dry.
Fusing point: 174-176 ℃
IR：3236，3089，2923，2867，2807，1562，1419，1407，1358，1322，1284，1154，1077，1002，814，742，680，569，504cm
-1
Embodiment 3:6-chloro-4-ethyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
Steps A: 6-chloro-4-ethyl-4H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
This compound can adopt monobromethane substituent methyl iodine to obtain according to the described method of embodiment 2 steps A.
Fusing point: 189-190 ℃
IR(KBr)：3098，2982，2943，2878，1609，1518，1480，1464，1437，1400，1300，1255，1173，1161，1121，1015，973，943，805，766，740，567，542cm
-1
Step B:6-chloro-4-ethyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
This compound can adopt above-mentioned steps A compound to obtain according to the described method of embodiment 2 step B.
Fusing point: 119-120 ℃
IR(KBr)：3235，2980，2931，2872，1558，1462，1448，1407，1360，1324，1154，1082，1010，798，742，678，570，501cm
-1
Embodiment 4:6-chloro-4-sec.-propyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
Steps A: 6-chloro-4-sec.-propyl-4H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
The compound of 400mg preparation 1 is dissolved in 8ml acetonitrile and several dimethyl formamides.Add 800mg salt of wormwood, add the 2-iodopropane of 0.6ml subsequently.With extremely about 55 ℃ of mixture heating up.After 8 hours, add the 2-iodopropane of 0.6ml again, reaction mixture is stirred spend the night.Evaporation removes desolvates and residue is water-soluble.The insoluble substance that obtains is collected after filtration fast, washed with water and be dissolved in the small amount of thermal methyl alcohol.Cooling obtains white crystal, collects after filtration, and is dry then with methanol wash.
Fusing point: 149-150 ℃
IR(KBr)：3112，2983，1605，1515，1458，1442，1407，1392，1306，1284，1170，1141，1095，1010，805，778，717，696，670，565，538cm
-1
Step B:6-chloro-4-sec.-propyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
Adopt above-mentioned steps A compound,, obtain this compound according to the described method of embodiment 2 step B.
Fusing point: 100-102 ℃
IR(KBr)：3267，3241，2970，2954，1545，1460，1445，1409，1332，1301，1156，1123，1025，786，742，692，678，566，502cm
-1
Embodiment 5:5,7-two chloro-3,4-dihydro-2H-thieno-[3,4-e] [1,2,4] thiadiazine 1,1-oxide compound
800mg is prepared 2 compounds be suspended in the 15ml water, and with 2g micro mist NaBH
4Slowly add.After 10 minutes, at room temperature stirred reaction mixture adopts 6N hydrochloric acid to be adjusted to pH 6 and also uses twice of dichloromethane extraction.Through dried over mgso organic phase and removal of solvent under reduced pressure.Residue is dissolved in small amount of methanol and uses activated carbon treatment, adds entry to precipitation then and forms.Then throw out is collected after filtration and be dissolved in small amount of methanol and add desalt twice.
Fusing point: 125-130 ℃
Embodiment 6:5,7-two chloro-4-methyl-3,4-dihydro-2H-thieno-[3,4-e] [1,2,4] thiadiazine 1,1-dioxide
Steps A: 5,7-two chloro-4-methyl-4H-thieno-[3,4-e] [1,2,4] thiadiazines 1,1-dioxide
200mg is prepared 2 compounds be dissolved in 2ml nitroethane and 2ml dimethyl formamide.Heated solution to 60 ℃.Add 0.2g salt of wormwood then, add the 0.2ml methyl iodide subsequently again.Stirred solution 2 hours.Removal of solvent under reduced pressure then.Residue is water-soluble.Insoluble substance is collected after filtration fast, washes with water and drying.
Fusing point: 202-207 ℃
IR(KBr)：3436，3043，2960，1607，1551，1472，1439，1400，1356，1347，1308，1202，1145，1101，1060，862，789，744，664，573，527cm
-1
Step B:5,7-two chloro-4-methyl-3,4-dihydro-2H-thieno-[3,4-e] [l, 2,4] thiadiazine 1,1-dioxide
In 60 ℃, 500mg above-mentioned steps A compound is dissolved in the 15ml Virahol.Then with 1.5g micro mist NaBH
4Add to solution.After 30 minutes, reduction vaporization is removed Virahol.Then that residue is water-soluble, with the pH regulator to 7 of solution.Use chloroform (3 * 40ml) extraction solutions then.Through the dried over mgso organic phase, filter then reduction vaporization to doing.Residue is dissolved in minimum of chloroform, slowly adds hexane to be settled out product.Product is collected after filtration, and is dry then with hexane wash.
Fusing point: 145-155 ℃ decomposition
IR(KBr)：3447，3231，2972，2821，1547，1465，1414，1328，1232，1180，1146，1090，1034，1002，975，746，661，565，556，525cm
-1
Embodiment 7:5,7-two chloro-4-ethyls-3,4-dihydro-2H-thieno-[3,4-e] [1,2,4] thiadiazine 1,1-dioxide
Steps A: 5,7-two chloro-4-ethyl-4H-thieno-[3,4-e] [1,2,4] thiadiazines 1,1-dioxide
The compound that 4g is prepared 2 step C places the 20ml triethyl orthoformate, and in 170 ℃ open vessel in heating 30 minutes.Then suspension is cooled off in ice.The throw out that forms is collected after filtration, with n-hexane wash and dry.
Fusing point: 172-175 ℃
Step B:5,7-two chloro-4-ethyls-3,4-dihydro-2H-thieno-[3,4-e] [1,2,4] thiadiazine 1,1-dioxide
0.5g above-mentioned steps A compound is dissolved in the 20ml Virahol.Solution is heated to 60 ℃, adds 1.5g micro mist NaBH again
4After 30 minutes, removal of solvent under reduced pressure.Then residue is dissolved in 30ml water, suspension adds the neutralization of 6N hydrochloric acid.With twice of chloroform extraction solution.Organic phase is through dried over mgso and removal of solvent under reduced pressure.Residue is dissolved in hexane, collects after filtration, with n-hexane wash and dry.
Fusing point: 144-147 ℃
Embodiment 8:6-chloro-N, 4-diethyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine-2-methane amide 1,1-dioxide
200mg embodiment 3 compounds are dissolved in 1.5mlCH
3CN.Then 1ml ethyl isocyanate and 0.2ml triethylamine are added to solution.At room temperature stirred reaction mixture is 2 hours.At last, solvent removed in vacuo.Residue is dissolved in small amount of acetone.Go out product through progressively adding water precipitation then.Product is collected after filtration fast, washes with water, and is dry then.
Fusing point: 80-81 ℃
Embodiment 9:6-chloro-N-ethyl-4-sec.-propyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4]-thiadiazine-2-methane amide 1,1-dioxide
According to embodiment 8 methods, adopt embodiment 4 compounds to replace embodiment 3 compounds, obtain this compound.
Fusing point: 72-74 ℃
Embodiment 10:5,7-two-chloro-N-ethyl-4-methyl-3,4-dihydro-2H-thieno-[3,4-e] [1,2,4]-thiadiazine-2-methane amide 1,1-dioxide
According to embodiment 8 methods, adopt embodiment 6 compounds to replace embodiment 3 compounds, obtain this compound.
Fusing point: 87-88 ℃
Embodiment 11:6-chloro-4-(2-fluoro ethyl)-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4]-thiadiazine 1,1-dioxide
Steps A: 6-chloro-4-(2-fluoro ethyl)-4H-thieno-[3,2-e] [1,2,4] thiadiazine 1, the 1-dioxide
The compound of 500mg preparation 1 is suspended in the 10ml acetonitrile.The 1-fluoro-2-iodoethane of 10 DMF, 1g salt of wormwood and 0.3ml is added in the suspension.In 70 ℃, stirring heating reaction mixture 35 hours.After the reaction mixture, remove by filter insoluble substance.Solvent removed by evaporation at reduced pressure.The solid residue that obtains is dissolved in 10ml water and collects rapidly after filtration.The product that obtains like this recrystallize in ethyl acetate.
Fusing point: 185-187 ℃
Step B:6-chloro-4-(2-fluoro ethyl)-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4]-thiadiazine 1,1-dioxide
The 100mg compound that above-mentioned steps A is obtained is dissolved in the 4ml Virahol.With mixture heating up to 60 ℃, add the 200mg sodium borohydride then.In this temperature after 10 minutes, solvent evaporated under reduced pressure.The residue that obtains is dissolved in 10ml water, and cooling and adding 6N hydrochloric acid are adjusted to pH4 in ice bath.Collect insoluble substance after filtration and wash with water.Then product is dissolved in minimum of chloroform, adds the n-hexane and be settled out product.Collecting precipitation thing after filtration then.
Fusing point: 141-144 ℃.
Embodiment 12:4,7-dimethyl-3,4-dihydro-2H-thieno-[2,3-e] [1,2,4] thiadiazine 1,1-dioxide
Steps A: 7-methyl-4H-thieno-[2,3-e] [1,2,4] thiadiazine 1,1-dioxide
2-amino-4-thiotolene-3-sulphonamide (according to the preparation of method described in the patent application WO 99/03861) of 200mg is dissolved in the 1.5ml trimethyl orthoformate.In 90 ℃ in open vessel in heating mixture 2 hours.Evaporate behind the decompression solvent, residue is dissolved in the 3ml ethyl acetate.The insolubles that obtains is collected after filtration, with ether washing and dry.
Fusing point: 195-198 ℃.
Step B:4,7-dimethyl-4H-thieno-[2,3-e] [1,2,4] thiadiazine 1,1-dioxide
To be suspended in the 5ml acetonitrile as the 150mg compound that above-mentioned steps A obtains.Add 300mg salt of wormwood and 0.15ml methyl iodide then.In 65 ℃ of heated and stirred reaction mixtures 30 minutes.After the solvent evaporated under reduced pressure, residue is dissolved in 5ml water, collects after filtration then, washes with water and drying.
Fusing point: 265-270 ℃.
Step C:4,7-dimethyl-3,4-dihydro-2H-thieno-[2,3-e] [1,2,4] thiadiazine 1,1-dioxide
The 240mg sodium borohydride is added in the compound that the 120mg above-mentioned steps B that is dissolved in the 6ml Virahol obtains.In 50 ℃ of heated mixt 10 minutes.Removal of solvent under reduced pressure is dissolved in 5ml water with the residue that obtains then.Add the pH regulator to 4 of 6N hydrochloric acid with solution.Throw out is collected after filtration, washes with water and drying.
Fusing point: 171-173 ℃.
Embodiment 13:6-chloro-4-isopropyl methyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4]-thiadiazine 1,1-dioxide
Steps A: 6-chloro-4-methyl fluoride-4H-thieno-[3,2-e] [1,2,4] thiadiazine 1,1-dioxide
The compound of 500mg preparation 1 is suspended in the 15ml acetonitrile.Add 500mg salt of wormwood and 1ml Bromofluoromethane then.With mixture place sealing autoclave and in 70 ℃ the heating 8 hours.Remove insoluble substance then after filtration.Behind the evaporating solvent, residue is dissolved in 20ml water and collects on strainer.With the solid that obtains like this by the methyl alcohol recrystallize.
Step B:6-chloro-4-isopropyl methyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4]-thiadiazine 1,1-dioxide
The 400mg sodium borohydride is added in the compound that the 200mg above-mentioned steps A that is suspended in the 8ml Virahol obtains.In 50 ℃ of stirring heating mixtures 10 minutes.Remove insoluble substance after filtration.After the solvent evaporated under reduced pressure, residue is dissolved in 1ml ethyl acetate/n-hexanes mixtures (15/5), in identical moving phase, through column chromatography purification.Behind the evaporating solvent, residue is dissolved in 1ml methyl alcohol, precipitates in water.Collect the solid product that obtains so after filtration, wash with water and drying.
Fusing point: 65-68 ℃.
The pharmaceutical research of The compounds of this invention
Embodiment A:
The excited electric current of AMPA inductive in the xenopus leavis oocytes (current) research
Adopted guanidine thiocyanate/phenol/chloroform method to prepare mRNA by the female Wistar rats cortex.On few dT Mierocrystalline cellulose, gather (A through chromatographic separation
+) mRNA, and with the horizontal injection of each ovocyte of 50ng.Ovocyte was cultivated 2-3 days so that expression of receptor in 18 ℃, and deposited in 8-10 ℃.
The electrophysiology record adopts Plexiglass
Chamber carry out in the OR2 medium in 20-24 ℃ (J.Exp.Zool., 1973,184,321-334), through " voltage clamp (voltage-clamp) " method, adopt two electrodes, the 3rd electrode places bath as reference.
All compounds all use by being dissolved in the developing medium, measure electric current when this end of processing.(S)-concentration of AMPA is 10 μ M.For each compound of studying, measure the concentration that makes strength of current increase twice (EC2 *) or five times (EC5 *) with respect to the independent inductive strength of current of AMPA (5-50nA).
The compounds of this invention has significantly strengthened the excitation of (S)-AMPA inductive.For example, the EC2 of embodiment 4-6 compound * and EC5 * value is as shown in the table:
| Compound | EC2×(μM) | EC5×(μM) |
| Embodiment 4 | 4.2±0.7 | 11±3 |
| Embodiment 6 | 5.4±2.8 | 11.3±4.9 |
Embodiment B:
Study by the excitatory postsynaptic potential (EPSP) (EPSP) that electricity irritation causes in the rat hippocampus part
The horizontal hippocampus part (500 μ M) of female Wistar rats can contain Mg then with organizing the blendor preparation
2+Incubation is 45 minutes in the not calcareous medium (10mM).Stable in being adjusted to the Krebs of pH7.35 then, at room temperature, use O
2/ CO
2(95%/5%) oxygenate.
This part in 30 ℃ of immersions, in the granulocytic dendroid of hippocampal dentate zone, is adopted per excitatory postsynaptic potential (EPSP) (EPSP) of wearing edge path (perforantpath) in 30 seconds in the bipolar pin tungsten electrode record stimulating course (50-100 μ A, 50 μ sec).
Obtain EPSP, and by A-D conversion device (converter), TL-1 interface and " pCLAMP " software analysis.
The amplitude of EPSP and time length adopt and estimate with respect to the negative wave (negative wave) of base current value.
Comprising MgSO
4Super fusion (1mM) is bathed in (superfusion bath) and was handled compound 10 minutes, with blocking-up nmda receptor activity.To each compound, mensuration makes PSEP increase by 50% amplitude (A50) or the concentration value of time length (D50).
The compounds of this invention has significantly increased the amplitude and the time length of the excitatory synapse current potential of rat hippocampus part.
Pharmaceutical composition:
1000 every pharmaceutical formulation that comprises the 10mg compound:
Embodiment 3 compound 10g
Hydroxypropylcellulose 2g
Wheat starch 10g
Lactose 100g
Magnesium Stearate 3g
Talcum powder 3g.
Claims (13)
1. the additive salt of formula (I) compound, their enantiomer and diastereomer and they and pharmaceutically acceptable acid or alkali:
Wherein:
◆ A forms with two carbon atoms that carry it:
Be selected from group A
1, A
2And A
3Thienyl, furyl or pyrryl group:
Wherein X represents sulphur, oxygen or nitrogen-atoms and R in each case
aAnd R
bCan be identical or different, represent hydrogen atom, straight or branched (C respectively independently of one another
1-C
6) alkyl group (optional replaced by one or more fluorine atoms), straight or branched (C
1-C
6) alkoxy base, halogen atom, oh group, amino group be (optional by straight or branched (C
1-C
6)-alkyl-carbonyl group, one or two straight or branched (C
1-C
6) alkyl group replaces), carboxylic group or straight or branched (C
1-C
6) alkoxycarbonyl groups,
Be selected from group A
4, A
5, A
6And A
7Oxygen thia cyclopentenes group:
R wherein
aDefinition as mentioned,
Be selected from group A
8And A
9Thiazolyl group:
R wherein
aDefinition as mentioned,
Be selected from group A
10And A
11The isothiazole group:
R wherein
aDefinition as mentioned,
Be selected from group A
12, A
13, A
14And A
15The oxazole group:
R wherein
aDefinition as mentioned,
Perhaps formula A
16Imidazole group:
R wherein
aDefinition as mentioned,
◆
Represent singly-bound or two key,
◆ R
1Represent hydrogen atom, optional by the straight or branched (C of one or more fluorine atoms or one or more halogen atom replacements except fluorine
1-C
6) alkyl group, perhaps (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl group, wherein each moieties can be straight or branched,
◆ R
2Represent hydrogen atom or optional by the straight or branched (C of one or more fluorine atoms or a plurality of halogen atoms replacements except fluorine
1-C
6) alkyl group,
◆ R
3Represent hydrogen atom or be selected from following group: straight or branched (C
1-C
6) alkyl, CONHR ' and SO
2NHR ', wherein R ' represents straight or branched (C
1-C
6) alkyl group.
2. the additive salt of the formula of claim 1 (I) compound, their enantiomer and diastereomer and they and pharmaceutically acceptable acid or alkali, wherein the A representative is selected from group A
1, A
2And A
3Thienyl group, wherein X represents sulphur atom.
3. the additive salt of claim 1 or 2 formula (I) compound, their enantiomer and diastereomer and they and pharmaceutically acceptable acid or alkali, wherein the A representative is selected from group A
1And A
2Thienyl group, wherein X represents sulphur atom.
4. the additive salt of claim 2 or 3 formula (I) compound, their enantiomer and diastereomer and they and pharmaceutically acceptable acid or alkali, wherein R
aAnd R
bIndependent each other hydrogen atom or the chlorine atom represented.
5. the additive salt of the formula of claim 1 (I) compound, their enantiomer and diastereomer and they and pharmaceutically acceptable acid or alkali, wherein R
1Represent hydrogen atom or straight or branched (C
1-C
6) alkyl group, preferable methyl, ethyl or isopropyl group.
6. the additive salt of the formula of claim 1 (I) compound, their enantiomer and diastereomer and they and pharmaceutically acceptable acid or alkali, wherein R
2Represent hydrogen atom.
7. the additive salt of the formula of claim 1 (I) compound, their enantiomer and diastereomer and they and pharmaceutically acceptable acid or alkali, wherein R
3Represent hydrogen atom or CONHR ', wherein R ' defines suc as formula (I).
8. the formula of claim 1 (I) compound is selected from:
6-chloro-4-ethyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1, the 1-dioxide,
6-chloro-4-sec.-propyl-3,4-dihydro-2H-thieno-[3,2-e] [1,2,4] thiadiazine 1, the 1-dioxide, and
5,7-two chloro-4-methyl-3,4-dihydro-2H-thieno-[3,4-e] [1,2,4] thiadiazine 1,1-dioxide.
9. the method for preparation formula (I) compound is a raw material with formula (II) compound:
Wherein A and
Suc as formula (I) definition,
In the presence of formula (III) compound, make the cyclisation of described formula (II) compound:
R
2-C(OMe)
3 (III)
R wherein
2Suc as formula (I) definition, obtain formula (IV) compound:
Wherein A, R
2With
As hereinbefore defined,
Make formula (IV) compound then:
● obtain formula (I/a) compound, the object lesson of a formula (I) compound with the reductive agent reaction:
Wherein A, R
2With
As hereinbefore defined,
Described formula (I/a) compound is optional to react with two carbonic acid two (tert-butyl) esters, obtains the formula V compound:
Wherein Boc represents group uncle-butoxy carbonyl and A, R
2With
As hereinbefore defined,
Described formula V compound and the reaction of formula (VI) compound:
R’
3-Y
3 (VI)
R ' wherein
3Represent straight or branched (C
1-C
6) alkyl group or CONHR ' or SO
2NHR ' group, wherein R ' defines suc as formula (I), and Y
3Represent leavings group, obtain formula (I/b) compound behind the deprotection, be an object lesson of formula (I) compound:
Wherein A, R
2, R '
3With
As hereinbefore defined,
● perhaps in alkaline medium, react with formula (VII) compound:
R’
1-Y
1 (VII)
R ' wherein
1Representative is optional by the straight or branched (C of one or more fluorine atoms or the replacement of a plurality of halogen atom
1-C
6) alkyl group, and Y
1Represent leavings group, obtain formula (VIII) compound:
Wherein A, R '
1, R
2With
As hereinbefore defined, described formula (VIII) compound and reductive agent reaction obtain formula (I/c) compound, are an object lesson of formula (I) compound:
Wherein A, R '
1, R
2With
As hereinbefore defined,
Described formula (I/c) compound is optional to react with formula mentioned above (VI) compound, obtains formula (I/d) compound, is an object lesson of formula (I) compound:
Wherein A, R '
1, R
2, R '
3With
As hereinbefore defined,
Described formula (I/a)-(I/d) compound has been formed the whole of formula (I) compound, if desired, can be according to the purification technique of routine, with these compound purifying, if desired, can they be separated into enantiomer or diastereomer according to the isolation technique of routine, and they can be converted into if desired, the additive salt of they and pharmaceutically acceptable acid or alkali.
10. pharmaceutical composition, this pharmaceutical composition comprise among the claim 1-8 the pharmaceutically acceptable carrier of each compound as activeconstituents and one or more inert non-toxic.
11. the pharmaceutical composition of claim 10 is used to prepare the medicine that treatment needs the disease of AMPA conditioning agent.
12. the pharmaceutical composition of claim 11 is as remembering and be familiar with promoted medicine.
13. the pharmaceutical composition of claim 11 is as the schizoid medicine of treatment.
Applications Claiming Priority (3)
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|---|---|---|---|
| FR0305448A FR2854634B1 (en) | 2003-05-05 | 2003-05-05 | NOVEL THIADIAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR03/05448 | 2003-05-05 | ||
| PCT/FR2004/001070 WO2004099217A1 (en) | 2003-05-05 | 2004-05-04 | Thiadiazine derivatives and use thereof as positive ampa receptor modulators |
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| EA (1) | EA009240B1 (en) |
| FR (1) | FR2854634B1 (en) |
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| AU2005280058B2 (en) | 2004-08-25 | 2010-09-02 | Essentialis, Inc. | Pharmaceutical formulations of potassium ATP channel openers and uses thereof |
| US7799777B2 (en) | 2006-01-05 | 2010-09-21 | Essentialis, Inc. | Salts of potassium ATP channel openers and uses thereof |
| US20110218190A1 (en) * | 2008-11-10 | 2011-09-08 | The Regents Of The University Of California | Therapeutic uses of ampa receptor modulators for treatment of motor dysfunction |
| JP5901365B2 (en) * | 2012-03-12 | 2016-04-06 | 株式会社トクヤマ | Method for producing imidate compound |
| EP3311842A1 (en) | 2013-06-13 | 2018-04-25 | VeroScience LLC | Compositions and methods for treating metabolic disorders |
| CA2991400C (en) | 2015-07-06 | 2020-05-12 | Public University Corporation Yokohama City University | Phenylsulphonamide derivatives useful as ampa receptor imaging agents |
| JP6241974B1 (en) | 2017-01-11 | 2017-12-06 | 公立大学法人横浜市立大学 | Imaging method, program and screening method for AMPA receptor in brain of primate organism |
| US10680583B1 (en) * | 2019-02-26 | 2020-06-09 | Xilinx, Inc. | Control circuit for and method of controlling an operation of an integrated circuit device |
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| US3733409A (en) * | 1969-05-20 | 1973-05-15 | Schering Corp | Method of treating hypertension using thieno (1,2,4) thiadiazines |
| AU4345297A (en) * | 1996-09-17 | 1998-04-14 | Regents Of The University Of California, The | Benzothiadiazide derivatives and their use as allosteric up-modulators of the ampa receptor |
| KR20010021936A (en) * | 1997-07-16 | 2001-03-15 | 한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느 | Fused 1,2,4-thiadiazine derivatives, their preparation and use |
| CA2320354A1 (en) * | 1998-02-18 | 1999-08-26 | Neurosearch A/S | Novel compounds and their use as positive ampa receptor modulators |
| FR2801587B1 (en) * | 1999-11-30 | 2002-01-11 | Adir | NOVEL BENZOTHIADIAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
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| CN103180326A (en) * | 2010-08-10 | 2013-06-26 | 武田药品工业株式会社 | Heterocyclic compound and use thereof |
| CN103180326B (en) * | 2010-08-10 | 2015-06-10 | 武田药品工业株式会社 | Heterocyclic compound and use thereof |
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| CN100363368C (en) | 2008-01-23 |
| MXPA05011823A (en) | 2006-05-25 |
| JP4461139B2 (en) | 2010-05-12 |
| FR2854634A1 (en) | 2004-11-12 |
| WO2004099217A1 (en) | 2004-11-18 |
| CA2524377C (en) | 2010-08-24 |
| BRPI0410002A (en) | 2006-04-25 |
| CA2524377A1 (en) | 2004-11-18 |
| NZ543214A (en) | 2009-02-28 |
| AU2004236005B2 (en) | 2010-01-21 |
| UA80046C2 (en) | 2007-08-10 |
| US7476668B2 (en) | 2009-01-13 |
| MY136694A (en) | 2008-11-28 |
| AU2004236005A1 (en) | 2004-11-18 |
| JP2006525292A (en) | 2006-11-09 |
| GEP20084318B (en) | 2008-03-10 |
| KR20060006830A (en) | 2006-01-19 |
| US20070004709A1 (en) | 2007-01-04 |
| ZA200508660B (en) | 2007-01-31 |
| EA200501696A1 (en) | 2006-06-30 |
| EP1620441A1 (en) | 2006-02-01 |
| EA009240B1 (en) | 2007-12-28 |
| MA27732A1 (en) | 2006-01-02 |
| NO20055695L (en) | 2005-12-01 |
| KR100741235B1 (en) | 2007-07-19 |
| HK1088327A1 (en) | 2006-11-03 |
| AR044245A1 (en) | 2005-09-07 |
| FR2854634B1 (en) | 2005-07-08 |
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